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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
DNMT inhibitors can inhibit DNA methylation and restore the expression of aberrantly silenced genes. 5-Azacytidine and 5-aza-2’-deoxycytidine are DNMT inhibitors clinically approved by for treating myelodysplastic syndrome. As mutations in metabolic enzymes, including IDH1/2, SDH and FH, drive tumorigenesis in part by promoting DNA hyper-methylation, inhibitors of DNMT might be useful for targeting tumors harboring these mutations. Both 5-azacytidine and 5-aza-2’-deoxycytidine has shown promising efficacy in targeting IDH1/2-mutant glioma in preclinical models. Borodovsky et al. (2013) showed that 5-azacytidine induced tumor regression in patient-derived xenografts from a patient with IDH1 mutant glioma. 5-Aza-2’-deoxycytidine effectively inhibited growth in IDH1-mutant glioma cells in vitro and xenografts (Turcan et al., 2013). Targeting methylome in combination with metabolic inhibitors for cancer treatment is currently being evaluated in Phase I/II studies in IDH1/2-mutant cancers.
Medium Design for Cell Culture Processing
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
Nucleosides and nucleic acid make up a very significant portion of a cell’s content, as they constitute the genome. Most cultured cells are diploid, although many industrial cell lines are multiploid. Nucleosides constitute all RNAs whose cellular content is higher than DNA. Additionally, free ribonucleotides, like ATP, ADP, and AMP, are present in relatively high abundance in the cell. In fast-growing cells, deoxyribonucleotides (deoxyadenosine, deoxyguanidine, deoxythymidine, deoxycytidine) and ribonucleotides (adenosine, guanidine, uridine, cytidine) must be synthesized sufficiently quickly or otherwise be supplied exogenously to sustain growth. Mammals have de novo synthesis pathways for making purines (adenosine and guanidine) and pyrimidines (uracil, cytidine, thymidine), although the major site of such synthesis is in the liver (Panel 7.16). Both bases (purine and pyrimidine) and nucleosides (base + ribose or deoxyribose, without phosphate) can be transported into cells from tissue fluid or culture medium. Cultured cells, notably cancer cells, can develop the capability to synthesize purines and pyrimidines. Nucleic acids, especially mRNAs, are subjected to degradation due to gene expression regulation and turned over rapidly in the cell. These degradation products, mostly nucleosides or nucleoside monophosphates, are recycled to nucleoside triphosphates through salvage pathways for incorporation into nucleic acids again.
Devising and Synthesis of NEMS and MEMS
Published in Sergey Edward Lyshevski, Nano- and Micro-Electromechanical Systems, 2018
As was emphasized, nucleic acids are polymers of monomers called nucleotides. Each nucleotide is itself composed of three parts (nitrogenous base is joined to a pentose that is bonded to a phosphate group). The DNA molecules consist of two polynucleotide chains (strands) that spiral around forming a double helix. These polynucleotide chains are held together by hydrogen bonds between the paired bases. DNA is a linear double-stranded polymer of four nitrogenous bases, i.e., Deoxyadenosine monophosphate or adenine (A)Deoxythymidine monophosphate or thymine (T) in DNA, and uracil (U) in RNADeoxyguanosine monophosphate or guanine (G)Deoxycytidine monophosphate or cytosine (C)
One-pot construction of gemcitabine loaded zeolitic imidazole framework for the treatment of lung cancer and its apoptosis induction
Published in Journal of Experimental Nanoscience, 2023
Zhan Li, Tiantian Du, Wen Yang, Shenni Yi, Na Zhang
Difluorodeoxycytidine (gemcitabine, termed GEM) is a pyrimidine antimetabolite chemically like deoxycytidine [8]. GEMs mode of action has been thoroughly studied and understood. Deoxycytidine kinase may convert GEM to dFdCMP, dFdCDP and dFdCTP or deoxycytidine deaminase can convert it to difluorodeoxyuridine [9]. The latter enters DNA and causes a break in the strand. Incorporating dFdCTP into DNA is less efficient than cytosine arabinoside (ara-C), so DNA exonuclease is more challenging to remove [10–12]. This likely adds to more intracellular accumulation of dFdCTP than ara-C, which may, in part, account for its distinct spectrum of preclinical and clinical action [13]. The enzyme ribonucleotide reductase, which generates the deoxynucleotides necessary for DNA synthesis, is also inhibited by GEM. Several human tumour xenografts and a wide range of mouse solid tumours and leukaemias respond to GEM treatment [14].
DNA-binding studies of a new Cu(II) complex containing reverse transcriptase inhibitor and anti-HIV drug zalcitabine
Published in Journal of Coordination Chemistry, 2019
Nahid Shahabadi, Amir Reza Abbasi, Ayda Moshtkob, Farshad Shiri
DNA is a primary intracellular target of antitumor drugs and plays a vital role in cellular progression such as transcription, translation, and replication, and thus, is the most significant target of many clinically used pharmaceuticals such as antiviral, anticancer, and antibacterial drugs. Antiviral drugs are a class of medication used specifically for treating viral infections [1]. Zalcitabine (2′-3′-dideoxycytidine) (ddC) is a nucleoside deoxycytidine, reverse transcriptase inhibitor (NRTI), and an antiviral drug that within cells converts to dideoxycytidine 5′-triphosphate (ddCTP) and loss of a 3′-OH group prevents formation of the 5′- to 3′-phosphodiester linkage essential for DNA chain elongation and, therefore, the viral DNA growth is terminated [2–4] and was used to treat human immunodeficiency virus (HIV) from 1992.
Genotoxicity of quinone: An insight on DNA adducts and its LC-MS-based detection
Published in Critical Reviews in Environmental Science and Technology, 2022
Yue Xiong, Han Yeong Kaw, Lizhong Zhu, Wei Wang
The most representative enzyme combination consists of DNase I, NP1, PDE I and ALP (Crain, 1990), which have been used in releasing DNA adducts formed form E1(E2)-3,4-Q (Embrechts et al., 2003), BPAQ (Zhao et al., 2018), B[a]PQ (Huang et al., 2013; Yao et al., 2017) and PBDE-Q (Lai et al., 2011). To ensure full reaction between these enzymes with the substrate, Crain’s method involved four distinctive adjustments of pH and temperatures, which are complicated and time-consuming. There are some other enzyme combinations for hydrolyzing DNA modification with less steps. Gackowski et al. proposed a two-step DNA hydrolysis method by using 1 U NP1 and 1.3 U ALP in 37 °C which only took two hours in total (Gackowski et al., 2016). Yin et al. mixed 1 U DNase I, 2 U ALP and 0.005 U SVP to hydrolyze 10 μg DNA overnight at 37 °C within a single step (Yin et al., 2013). Quinlivan and Gregory also proposed a one-step enzymatic hydrolysis method by digesting 1 μg DNA sample with 50 μL digest mix to achieve complete hydrolysis after incubating at 37 °C (Quinlivan & Gregory, 2008). The digest mix was prepared in advance by dissolving benzonase, phosphodiesterase I and alkaline phosphatase in Tris-HCl buffer containing NaCl and MgCl2, which aided in realizing high throughput hydrolysis. Nonetheless, it is worth noticing that these methods aimed to release DNA methylations, such as 5-methyl-2′-deoxycytidine (5mC), 5-(hydroxymethyl)-2′-deoxycytidine (5hmC) and 5-formyl-2′-deoxycytidine (5fC) etc., but the practicality of applying these methods to analyze quinone-induced DNA adducts requires further experimental proof.